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    Clinical Trial Results:
    A MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, PARALLEL GROUP PHASE 2A STUDY TO ASSESS THE EFFICACY OF RO5459072 IN PATIENTS WITH PRIMARY SJÖGREN’S SYNDROME

    Summary
    EudraCT number
    		 2015-004476-30
    Trial protocol
    		 GB   PT   DE   PL   FR  
    Global end of trial date
    10 Jul 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Jun 2018
    First version publication date
    14 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BP30037
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02701985
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a randomized, double-blind, placebo-controlled, two-treatment arm, parallel-group study designed to evaluate the effects of RO5459072 treatment on disease activity and symptoms of Sjogren's syndrome in adult participants with moderate to severe primary Sjogren's syndrome. The total duration of the study for each participant will be approximately 18 weeks (including screening).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Jul 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    75
    EEA total number of subjects
    53
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    64
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 75 patients were randomized in a 1:1 ratio to RO5459072 or placebo (38 patients in the RO5459072 treatment group and 37 patients in the placebo group).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Matching-placebo capsules was administered orally, 2 times a day, for up to 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Matching-placebo capsules was administered orally, 2 times a day with food.

    Arm title
    		 RO5459072
    Arm description
    		 RO5459072 at a dose of 100 milligrams (as capsules) was administered orally, 2 times a day, for up to 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO5459072
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    RO5459072 at a dose of 100 milligrams (as capsules) was administered orally, 2 times a day with food.

    Number of subjects in period 1
    		Placebo RO5459072
    Started
    37
    38
    Completed
    34
    32
    Not completed
    3
    6
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    -
    5
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching-placebo capsules was administered orally, 2 times a day, for up to 12 weeks.

    Reporting group title
    RO5459072
    Reporting group description
    		 RO5459072 at a dose of 100 milligrams (as capsules) was administered orally, 2 times a day, for up to 12 weeks.

    Reporting group values
    		 Placebo RO5459072 Total
    Number of subjects
    		 37 38 75
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 32 32 64
        From 65-84 years
    		 5 6 11
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.3 ( 11.8 ) 52.1 ( 13.2 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 36 32 68
        Male
    		 1 6 7
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 3 2 5
        White
    		 33 35 68
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 0 2
        Not Hispanic or Latino
    		 35 38 73
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching-placebo capsules was administered orally, 2 times a day, for up to 12 weeks.

    Reporting group title
    RO5459072
    Reporting group description
    		 RO5459072 at a dose of 100 milligrams (as capsules) was administered orally, 2 times a day, for up to 12 weeks.

    Primary: Percentage of Participants With a Clinically Relevant Decrease in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Score

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    End point title
    		 Percentage of Participants With a Clinically Relevant Decrease in European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) Score
    End point description
    The efficacy of RO5459072 in patients with primary Sjogren's Syndrome Disease is evaluated in terms of the percentage of participants with a clinically relevant decrease in ESSDAI Score, where a clinically relevant decrease in ESSDAI score is defined as a decrease of ≥ 3 points.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Percentage of Participants
        number (confidence interval 95%)
    37.8 (20.86 to 54.86)
    42.1 (25.09 to 59.12)
    Statistical analysis title
    		 Comparison of Placebo and RO5459072
    Statistical analysis description
    The proportion of patients who have ≥ 3 point reduction from baseline in ESSDAI score after 12 weeks of treatment was compared between the two treatment arms using a Pearson Chi-square test (two sided p-values, alpha 0.05). The difference in proportions and corresponding 95% confidence interval (CI) are provided. Patients with missing data at Week 12 will be treated as non-responders in the analysis.
    Comparison groups
    RO5459072 v Placebo
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.7955
    Method
    		 Chi-square with Schouten Correction
    Parameter type
    		 Difference in Response Rates
    Point estimate
    4.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.55
         upper limit
    		 29.08

    Secondary: Percentage of Participants With a Clinically Relevant Decrease in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) Score

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    End point title
    		 Percentage of Participants With a Clinically Relevant Decrease in EULAR Sjogren's Syndrome Patient-Reported Index (ESSPRI) Score
    End point description
    The efficacy of RO5459072 in patients with primary Sjogren's Syndrome Disease is evaluated in terms of the percentage of participants with a clinically relevant decrease in ESSPRI Score, where a clinically relevant decrease in ESSPRI score is defined as a decrease of ≥ 1 point.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Percentage of Participants
        number (confidence interval 95%)
    56.8 (39.44 to 74.07)
    57.9 (40.88 to 74.91)
    No statistical analyses for this end point

    Secondary: Change From Baseline in ESSDAI Score at Week 12

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    End point title
    		 Change From Baseline in ESSDAI Score at Week 12
    End point description
    Change from baseline in ESSDAI Score is defined as the change in score between baseline (Week -1) and Week 12. The ESSDAI is a physician-assessed disease activity index for primary Sjögren’s syndrome developed by the EULAR consortium. It consists of 44 items in 12 organ-specific ‘domains’ contributing to disease activity (constitutional, lymphadenopathy, articular, muscular, cutaneous, glandular, pulmonary, renal, peripheral nervous system [PNS], central nervous system [CNS], hematological, biological). Each domain is assessed for activity level (i.e., no, low, moderate, high) and assigned a numerical score based on pre-determined weighting of each individual domain. An overall score is then calculated as the sum of all individual weighted domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1), Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline in ESSDAI Score|
    11.27 ( 5.71 )
    11.79 ( 4.69 )
        Change From Baseline in ESSDAI Score at Week 12|
    -3.06 ( 3.96 )
    -3.25 ( 4.09 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in ESSPRI Score at Week 12

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    End point title
    		 Change From Baseline in ESSPRI Score at Week 12
    End point description
    Change from baseline in ESSPRI Score is defined as the change in score between baseline (Week -1) and Week 12. The ESSPRI is a patient-reported, subjective symptom index for primary Sjögren’s syndrome developed by the EULAR consortium. It consists of three questions covering the cardinal symptoms of Sjögren’s syndrome: dryness, fatigue and pain (articular and/or muscular). Each domain scored on scale of 0-10, and an overall score is calculated as the mean of the three individual domains where all domains carry the same weight.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1), Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline in ESSPRI Score|
    7.34 ( 1.19 )
    6.98 ( 0.98 )
        Change From Baseline in ESSPRI Score at Week 12|
    -1.35 ( 1.67 )
    -1.51 ( 1.79 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Score at Week 12

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    End point title
    		 Change From Baseline in Short Form 36 Health Survey (SF-36) Mental Score at Week 12
    End point description
    Change from baseline in Short Form-36 Health Survey (SF-36) Mental score is defined as the change in score between baseline (Week -1) and Week 12. The SF-36 was used to assess health-related quality of life at baseline and at on-treatment visits. The SF-36 consisted of 36 questions covering 8 domains (general health, physical functioning, role-functioning physical, bodily pain, social functioning, role-functioning emotional, mental health, and vitality), with each domain scoring on a scale 0-100. Reported here is the mental health domain score.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1), Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    42.09 ( 11.18 )
    40.52 ( 9.27 )
        Change from Baseline at Week 12|
    4.52 ( 7.15 )
    3.02 ( 9.04 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in SF-36 Physical Score at Week 12

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    End point title
    		 Change From Baseline in SF-36 Physical Score at Week 12
    End point description
    Change from baseline in SF-36 Physical Score is defined as the change in score between baseline (Week -1) and Week 12. The SF-36 was used to assess health-related quality of life at baseline and at on-treatment visits. The SF-36 consisted of 36 questions covering 8 domains (general health, physical functioning, role-functioning physical, bodily pain, social functioning, role-functioning emotional, mental health, and vitality), with each domain scoring on a scale 0-100.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1), Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline in SF-36 Physical Score|
    40.86 ( 6.82 )
    40.71 ( 6.94 )
        Change From Baseline at Week 12|
    2.46 ( 6.09 )
    3.01 ( 5.10 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in ESSPRI Dryness Component Score at Week 12

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    End point title
    		 Change From Baseline in ESSPRI Dryness Component Score at Week 12
    End point description
    Change from baseline in ESSPRI dryness component score is defined as the change in score between baseline (Week -1) and Week 12.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1), Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    7.54 ( 1.57 )
    7.45 ( 1.25 )
        Change From Baseline at Week 12|
    -1.15 ( 1.56 )
    -1.77 ( 2.29 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in ESSPRI Fatigue Component Score at Week 12

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    End point title
    		 Change From Baseline in ESSPRI Fatigue Component Score at Week 12
    End point description
    Change from baseline in ESSPRI fatigue component score is defined as the change in score between baseline (Week -1) and Week 12. The ESSPRI score consists of three questions covering the cardinal symptoms of Sjögren’s syndrome: dryness, fatigue and pain (articular and/or muscular). Each domain scored on scale of 0-10.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1), Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    7.22 ( 1.81 )
    7.24 ( 1.84 )
        Change From Baseline at Week 12|
    -1.29 ( 2.24 )
    -1.94 ( 2.16 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in ESSPRI Pain Component Score at Week 12

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    End point title
    		 Change From Baseline in ESSPRI Pain Component Score at Week 12
    End point description
    Change from baseline in ESSPRI pain component score is defined as the change in score between baseline (Week -1) and Week 12. The ESSPRI score consists of three questions covering the cardinal symptoms of Sjögren’s syndrome: dryness, fatigue and pain (articular and/or muscular). Each domain scored on scale of 0-10.
    End point type
    Secondary
    End point timeframe
    Baseline (Week -1), Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    7.27 ( 1.71 )
    6.26 ( 2.05 )
        Change From Baseline at Week 12|
    -1.62 ( 2.70 )
    -0.97 ( 2.56 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Tear Flow Rate at Weeks 2, 6, and 12

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    End point title
    		 Change From Baseline in Tear Flow Rate at Weeks 2, 6, and 12
    End point description
    Un-stimulated tear production rate was measured from both eyes (without the use of analgesics/ anesthetic drops) at baseline and at on-treatment visits using the Schirmer method. A thin strip of filter paper (Schirmer strip, e.g., 35 x 5 mm) was placed at the junction of the lateral and middle thirds of the lower eyelid of each eye. The maximum length of wetting along the strip at the end of the test period was measured.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 6, and Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: volume/time
    arithmetic mean (standard deviation)
        Baseline in Tear Flow Rate|
    7.53 ( 9.66 )
    7.84 ( 10.15 )
        Change from Baseline at Week 2|
    -0.54 ( 5.02 )
    -0.81 ( 5.06 )
        Change from Baseline at Week 6|
    -1.39 ( 6.32 )
    -0.95 ( 7.95 )
        Change from Baseline at Week 12|
    -2.38 ( 6.47 )
    -1.65 ( 7.71 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Mechanically Stimulated Salivary Flow Rate at Weeks 2, 6, and 12

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    End point title
    		 Change From Baseline in Mechanically Stimulated Salivary Flow Rate at Weeks 2, 6, and 12
    End point description
    Change from baseline in mechanically stimulated salivary flow rate is defined as the change in flow (mL/min) between baseline (Week -1) and Week 2, Week 6 and Week 12. Using a mechanical stimulation method of a piece of neutral wax, paraffin, silicone, unflavored chewing gum, or similar chewable, unflavored, nonabsorbent material, patients were instructed to chew for a period of 5 minutes. The stimulated salivary flow rate was calculated assuming a specific gravity of 1 (i.e., 1 mL saliva = 1 g) and expressed in mL per minute.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 6, and Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: mL/min
    arithmetic mean (standard deviation)
        Baseline|
    0.45 ( 0.29 )
    0.55 ( 0.58 )
        Change from Baseline at Week 2|
    0.10 ( 0.33 )
    -0.01 ( 0.33 )
        Change from Baseline at Week 6|
    0.10 ( 0.31 )
    0.11 ( 0.47 )
        Change from Baseline at Week 12|
    0.12 ( 0.30 )
    0.24 ( 0.75 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Anti-Sjögren's-Syndrome-Related Antigen A at Weeks 6, and 12

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    End point title
    		 Change From Baseline in Anti-Sjögren's-Syndrome-Related Antigen A at Weeks 6, and 12
    End point description
    Anti-Sjögren's-syndrome-related antigen A is a type of antibody found in the auto-antibody titers.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6, and Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: U/mL
    arithmetic mean (standard deviation)
        Baseline|
    214.52 ( 58.06 )
    217.78 ( 53.96 )
        Change from Baseline at Week 6|
    -4.82 ( 16.05 )
    -1.47 ( 13.90 )
        Change from Baseline at Week 12|
    -2.57 ( 18.97 )
    -5.20 ( 11.65 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Anti-Sjögren's-Syndrome-Related Antigen B at Weeks 6, and 12

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    End point title
    		 Change From Baseline in Anti-Sjögren's-Syndrome-Related Antigen B at Weeks 6, and 12
    End point description
    Anti-Sjögren's-syndrome-related antigen B is a type of antibody found in the auto-antibody titers.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6, and Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: U/mL
    arithmetic mean (standard deviation)
        Baseline|
    101.66 ( 130.48 )
    76.94 ( 120.76 )
        Change from Baseline at Week 6|
    1.94 ( 15.20 )
    -2.55 ( 13.09 )
        Change from Baseline at Week 12|
    1.35 ( 13.52 )
    -4.47 ( 12.32 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Rheumatoid Factor at Weeks 6, and 12

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    End point title
    		 Change From Baseline in Rheumatoid Factor at Weeks 6, and 12
    End point description
    Rheumatoid factor is a type of auto-antibody found in the auto-antibody titers.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6, and Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: kU/L
    arithmetic mean (standard deviation)
        Baseline in Rheumatoid Factor|
    43.00 ( 48.51 )
    117.84 ( 336.82 )
        Change from Baseline at Week 6|
    -1.50 ( 10.74 )
    -28.03 ( 70.04 )
        Change from Baseline at Week 12|
    -0.68 ( 9.97 )
    -57.77 ( 173.75 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Immunoglobulin G (IgG) at Weeks 6, and 12

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    End point title
    		 Change From Baseline in Total Immunoglobulin G (IgG) at Weeks 6, and 12
    End point description
    Total IgG is a type of auto-antibody found in the auto-antibody titers.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6, and Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: g/L
    arithmetic mean (standard deviation)
        Baseline in Total IgG|
    15.74 ( 6.77 )
    13.59 ( 4.92 )
        Change from Baseline at Week 6|
    0.11 ( 1.51 )
    -0.30 ( 1.21 )
        Change from Baseline at Week 12|
    0.48 ( 1.78 )
    -0.50 ( 1.13 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Total Immunoglobulin M (IgM) at Weeks 6, and 12

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    End point title
    		 Change From Baseline in Total Immunoglobulin M (IgM) at Weeks 6, and 12
    End point description
    Total IgM is a type of auto-antibody found in the auto-antibody titers.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 6, and Week 12
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: g/L
    arithmetic mean (standard deviation)
        Baseline in Total IgM|
    1.24 ( 0.82 )
    1.26 ( 0.75 )
        Change from Baseline at Week 6|
    0.03 ( 0.20 )
    -0.10 ( 0.17 )
        Change from Baseline at Week 12|
    0.06 ( 0.25 )
    -0.17 ( 0.20 )
    No statistical analyses for this end point

    Secondary: Minimum Concentration (Cmin) of RO5459072

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    End point title
    		 Minimum Concentration (Cmin) of RO5459072 [1]
    End point description
    Minimum observed plasma concentration (mass/volume)
    End point type
    Secondary
    End point timeframe
    Week 2, Week 6, and Week 12
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only analyzing the minimum concentration of RO5459072
    End point values
    		 RO5459072
    Number of subjects analysed
    38
    Units: ng/mL
        median (confidence interval 90%)
    1340 (2.68 to 2900)
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of RO5459072

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    End point title
    		 Maximum Concentration (Cmax) of RO5459072 [2]
    End point description
    Maximum observed plasma concentration (mass/volume)
    End point type
    Secondary
    End point timeframe
    Week 2, Week 6, and Week 12
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only analyzing the max concentration of RO5459072
    End point values
    		 RO5459072
    Number of subjects analysed
    38
    Units: ng/mL
        median (confidence interval 90%)
    2350 (1140 to 3610)
    No statistical analyses for this end point

    Secondary: Average Concentration (Caverage) of RO5459072

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    End point title
    		 Average Concentration (Caverage) of RO5459072 [3]
    End point description
    Average observed plasma concentration (mass/volume)
    End point type
    Secondary
    End point timeframe
    Week 2, Week 6, and Week 12
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was only analyzing the average concentration of RO5459072
    End point values
    		 RO5459072
    Number of subjects analysed
    38
    Units: ng/mL
        median (confidence interval 90%)
    1740 (816 to 3187)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events

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    End point title
    		 Percentage of Participants With Adverse Events
    End point description
    An adverse event is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 14
    End point values
    		 Placebo RO5459072
    Number of subjects analysed
    37
    38
    Units: Participants
        number (not applicable)
    78.4
    76.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The total duration of the study for each patient was (up to) 19 weeks.
    Adverse event reporting additional description
    The safety population is defined as all patients who received at least one dose of the study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching-placebo capsules was administered orally, 2 times a day, for up to 12 weeks.

    Reporting group title
    RO5459072
    Reporting group description
    		 RO5459072 at a dose of 100 milligrams (as capsules) was administered orally, 2 times a day, for up to 12 weeks.

    Serious adverse events
    		 Placebo RO5459072
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 38 (2.63%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Cardiac Arrest
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 37 (0.00%)
    1 / 38 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Metabolic Acidosis
         subjects affected / exposed
    1 / 37 (2.70%)
    0 / 38 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo RO5459072
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 37 (51.35%)
    25 / 38 (65.79%)
    Investigations
    Blood Thyroid Stimulating Hormone Decreased
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 37 (10.81%)
    5 / 38 (13.16%)
         occurrences all number
    5
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 38 (7.89%)
         occurrences all number
    1
    5
    Diarrhoea
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 38 (5.26%)
         occurrences all number
    2
    2
    Dyspepsia
         subjects affected / exposed
    2 / 37 (5.41%)
    0 / 38 (0.00%)
         occurrences all number
    2
    0
    Nausea
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 38 (13.16%)
         occurrences all number
    0
    6
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 37 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    2
    Pruritus
         subjects affected / exposed
    2 / 37 (5.41%)
    2 / 38 (5.26%)
         occurrences all number
    2
    3
    Rash
         subjects affected / exposed
    1 / 37 (2.70%)
    5 / 38 (13.16%)
         occurrences all number
    1
    5
    Urticaria
         subjects affected / exposed
    0 / 37 (0.00%)
    5 / 38 (13.16%)
         occurrences all number
    0
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 37 (2.70%)
    3 / 38 (7.89%)
         occurrences all number
    1
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 37 (5.41%)
    1 / 38 (2.63%)
         occurrences all number
    2
    1
    Influenza
         subjects affected / exposed
    1 / 37 (2.70%)
    2 / 38 (5.26%)
         occurrences all number
    1
    2
    Sinusitis
         subjects affected / exposed
    3 / 37 (8.11%)
    1 / 38 (2.63%)
         occurrences all number
    4
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 37 (5.41%)
    5 / 38 (13.16%)
         occurrences all number
    2
    8
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 37 (5.41%)
    6 / 38 (15.79%)
         occurrences all number
    2
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2016
    The instructions that the patients need to be fasted prior to safety laboratory tests was added to laboratory assessments. The list of MDR1 (P-gp) inhibitors was updated and restricted to only those medications which are potent inhibitors in vivo.
    30 Oct 2016
    The eligibility criteria of the protocol was amended to mandate testing for tuberculosis and exclude patients with positive results and excluded women who are breast-feeding or planning to nurse. The eligibility criteria was amended to explicitly exclude patients who are using strong inhibitors of CYP3A4 and P-glycoprotein (P-gp), as well as compounds inducing CYP3A4. Measurement of bicarbonate was added to the laboratory test panel. Total IgM was added to the list of antibody titres to be measured. As samples for the above were not collected at all visits where ESSDAI was evaluated, additional assessment time points for cryoglobulin, IgG and IgM was added to the Schedule of Assessment and the complement C3/4 assessment was moved to the blood biochemistry panel. A section on interpretation and reporting of abnormal liver function tests was inserted to provide more specific guidance for investigators. The alpha level for any hypothesis testing was clarified as 2-sided at the 0.05 level to align with the use of 95% confidence intervals. Additionally the primary analysis used a non-responder approach for missing data and an exploratory analysis was pre-specified adjusting for baseline ESSDAI score.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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